Systemic Illnesses Involving the Gastrointestinal Tract

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Chapter 6

Systemic Illnesses Involving the Gastrointestinal Tract

David N.B. Lewin

Introduction

Systemic illnesses commonly affect the gastrointestinal (GI) tract. GI symptoms and morphologic changes can result from several different pathogenetic mechanisms, such as nonspecific or constitutional symptoms, pathologic changes common to intestinal and extraintestinal organs, secondary changes such as opportunistic infections or drug reactions, and metastatic disease. This chapter focuses on morphologic alterations in the GI tract resulting from disorders that primarily affect other organ systems.

Cardiovascular Disorders

Cardiac Surgery and Heart Transplantation

GI complications after open heart surgery are uncommon, occurring in approximately 1% of cases; however, the mortality rate is high (approximately 30%).1,2 Clinical features typically consist of GI hemorrhage secondary to stress ulceration, vascular insufficiency with ischemic necrosis of bowel, and acute diverticulitis. Additional risk factors for ischemia include end-stage renal disease, female sex, non–coronary artery bypass graft, and long pump times.2

In contrast to GI complications after open heart surgery, GI complications after cardiac transplantation have been reported in as many as 20% of patients.3,4 Complications include all of the hemorrhagic conditions mentioned previously. In addition, the use of steroids and immunosuppressive agents increases the risks of intestinal perforation, fistula formation, and infectious GI diseases. These patients are also at risk for posttransplantation lymphoproliferative disorders5 (see Chapter 52).

Ischemic Disease

Intestinal ischemic disease can be divided into two major subsets: nonthrombotic (approximately 60% of cases) and thrombotic (approximately 40% of cases).6 Nonthrombotic causes of ischemic disease include decreased mesenteric blood flow secondary to cardiac failure, shock, atherosclerotic vascular disease, disseminated intravascular coagulation, vasculitis, and fibromuscular dysplasia. Thrombotic causes can be divided into arterial embolism, arterial thrombosis, and venous thrombosis. These are a heterogeneous group of disorders usually seen in elderly individuals.7 Colonic ischemia, the most common disorder (typically nonthrombotic), has a favorable prognosis. Acute mesenteric ischemia, in contrast, has a poor prognosis, with a survival rate of only 50%.6 Histologically, resultant lesions range from epithelial and lymphocytic apoptosis8 to mucosal necrosis and transmural infarction of the bowel (Fig. 6.1). Specifics concerning histology and pathology are discussed in Chapter 10.

Dermatologic Disorders

Both the skin and the GI tract may become involved in a variety of disease processes. These lesions may be divided as follows:

Bullous Diseases

The majority of primary dermatologic bullous disorders that involve the GI tract occur in conjunction with a skin disorder (excluding dermatitis herpetiformis). These diseases typically involve the upper portion of the esophagus. Patients are seen with symptoms of dysphagia and odynophagia. Histologically, the lesions in esophageal squamous mucosa appear similar to those in the skin. The key distinguishing morphologic features are the level of the plane of separation (vesicle formation), the type of inflammatory infiltrate, and the presence or absence of acantholysis.9 Because the bullae rarely remain intact, diagnosis of these lesions on GI biopsy specimens is challenging. The diagnosis is usually made on the basis of appropriate clinical information combined with biopsies of the skin lesions. In the esophagus, lesions often rupture and produce erosions; occasionally, fibrosis and stricture formation are also seen.

Epidermolysis Bullosa

Epidermolysis bullosa, a group of more than 12 genetically determined disorders that involve all organs lined by squamous epithelium,10 is characterized by the formation of vesiculobullous lesions secondary to minor trauma. The site of cleavage can be in the dermis (dermolytic or dystrophic form), at the dermoepidermal junction (junctional form), or in the epidermis (epidermolytic or simplex form). Involvement of the GI tract occurs in 50% of patients with the dystrophic form and in 33% of those with the junctional or simplex form.11 Stricture and esophageal webs occur most frequently in the dystrophic form but can also be seen rarely in the junctional or simplex form.12 In addition, anal and perianal disease and perianal blistering are seen in all types. Histologically, this lesion is characterized by separation of the epithelium and formation of bullae, with little or no inflammatory infiltrate.

Epidermolysis bullosa aquisita is a rare acquired disorder with clinical characteristics similar to those of epidermolysis bullosa except for adult onset, milder skin disease, and lack of family history. It may be associated with systemic diseases such as amyloidosis, multiple myeloma, diabetes mellitus, and inflammatory bowel disease (IBD). A subset of patients have circulating immunoglobulin G (IgG) that recognizes collagen IV. Endoscopic biopsy may show linear deposition of IgG in the basement membrane.

Pemphigus Vulgaris

Pemphigus vulgaris is a bullous disorder that affects middle-aged and older individuals. The bullae are superficial and flaccid. The lesion is an intraepidermal bulla formed by acantholysis (loss of intracellular bridges). Histologically, the cells lose their normal angular contours and become rounded. Basal keratinocytes typically remain attached to the epidermal basement membrane. The inflammatory infiltrate is variable; eosinophils and lymphocytes are the cells most commonly present in the epidermis, both surrounding and within the bullae and within the subjacent lamina propria. Standard biopsy forceps may provide only superficial specimens that are inadequate for diagnosis.13 Direct immunofluorescence for immunoglobulins and complement component C3 is positive in the epidermal intercellular spaces.14 The incidence of esophageal involvement is unclear. Some studies report endoscopic lesions in as much as 80% of patients.15,16 In addition, immunofluorescence performed on esophageal mucosa is usually positive in all patients with active disease.17

Bullous Pemphigoid

Bullous pemphigoid is a subepidermal bullous disorder characterized by large, tense blisters on the skin. Mucosal involvement of the GI tract is much less common than in pemphigus vulgaris,18 although one report described esophageal blisters in 4% of patients with typical bullous pemphigoid.19 The histology of the bullous lesion has not been described. However, linear deposits of IgG and complement in the basement membrane of the esophagus and occasionally in the stomach, similar to those found in the skin, have been described.18 A single case of bullae in the colon has also been reported.20

Cicatricial pemphigoid (benign mucous membrane pemphigoid) is an autoimmune bullous disease related to bullous pemphigoid. It has similar immunohistochemical linear deposition of C3 and IgG. The circulating autoantibodies recognize bullous pemphigoid antigen 2 (BPAC2). Esophageal involvement has been reported in approximately 4% of patients with the disease.21

Erythema Multiforme

Erythema multiforme, as the name implies, is a cutaneous reaction pattern characterized by a combination of skin and mucosal lesions. The mucosal lesions usually occur on the lips or in the oral cavity and conjunctiva. However, the esophagus and, rarely, other regions of the GI tract may be involved.22 Included in this group of disorders is the Stevens-Johnson syndrome (macular trunk lesions with mucosal involvement).23 Many of these lesions occur secondary to drug reactions (type IV hypersensitivity reactions) or, occasionally, reactions to infectious agents such as mycoplasmae. In the esophagus, lesions have been described as small white patches similar to those caused by Candida spp. infection. Histologically, superficial ulceration and marked intraepithelial lymphocytosis are often observed. Individual squamous cell necrosis most often involves the basal cells but may also include the entire thickness of the epithelium. Lesions typically regress; therefore, GI complications usually are not sampled for biopsy.

Hailey-Hailey and Darier Diseases

Hailey-Hailey disease, also known as benign familial pemphigus, is a rare disorder with an autosomal dominant inheritance pattern. Patients typically are seen in the fourth to fifth decade of life with blistering and crusting skin lesions in intertriginous zones. Mucous membrane involvement is rare but may occur. Darier disease is similar to Hailey-Hailey disease, but its onset is typically in the first to second decade of life. Histologic features of both include dyskeratosis, suprabasal acantholysis, papillomatosis, and suprabasal separation with loss of intracellular bridges. Darier disease more commonly involves the esophagus.24

Dermatitis Herpetiformis

Dermatitis herpetiformis is a pruritic vesicular dermatitis with a symmetric distribution on the skin. Unlike the previously discussed bullous disorders of the skin, this disease does not produce bullous lesions in the GI tract. Dermatitis herpetiformis is strongly associated with celiac disease. Approximately 70% of patients with dermatitis herpetiformis show evidence of villous atrophy on small bowel biopsy.25 However, most patients are asymptomatic. Of patients with dermatitis herpetiformis, 90% are positive for endomysial autoantibodies26 (typically seen with celiac sprue as well). Human leukocyte antigen associations are similar for both dermatitis herpetiformis and celiac sprue. Both the skin disease and the GI symptoms can be controlled by a gluten-free diet.27

Dermatogenic Enteropathy

Many GI symptoms and histologic findings have been described in patients with active psoriasis and eczema. Steatorrhea and malabsorption are not uncommon, and the terms dermatogenic enteropathy and psoriatic enteropathy have been applied to these syndromes.28,29 Histologically, the duodenal mucosa shows an increase in the numbers of mast cells and eosinophils. A subset of patients have increased numbers of duodenal intraepithelial lymphocytes and antibodies to gliadin (suggestive of latent celiac sprue).30 In addition, the colon may show increased lamina propria cellularity, active inflammation, and occasional gland atrophy in mucosal biopsy specimens from patients who have psoriasis without bowel symptoms.31

Dermatologic Disorders Associated with Malignancies of the GI Tract

Acanthosis Nigricans

Acanthosis nigricans consists of numerous brown, hyperpigmented, velvety skin plaques located in the axillae, groin, and flexural areas. The lesion has two major forms—one associated with internal malignancies and the other associated with insulin resistance. Microscopically, dermal lesions are characterized by diffuse hyperkeratosis and papillomatosis. Epithelial hyperplasia of the esophagus also has been described.

When present, this lesion is usually associated with adenocarcinomas of the stomach and colon. At least one report has suggested that it is caused by the production of transforming growth factor-α by tumor cells.32

Tylosis

Focal nonepidermolytic palmoplantar keratoderma (tylosis) is a rare, autosomal dominant, inherited defect of keratinization. It is strongly associated with the development of squamous cell carcinoma of the esophagus, with tumors appearing in 95% of patients.33 The skin lesion is characterized by thickening of the stratum corneum of the palms and soles. The esophageal mucosa in tylosis is typically affected by papillomatosis, which appears as multiple small protrusions, some with spines due to acanthosis. Molecular studies have mapped the defective gene to a small region on chromosome 17q25.34,35 The same region has been implicated in the development of sporadic squamous cell carcinoma and Barrett esophagus–associated adenocarcinoma.

Miscellaneous Disorders

Several other nonspecific skin diseases are associated with GI neoplasms.36 These diseases include generalized dermal pigmentation, migratory thrombophlebitis, and seborrheic keratosis (Leser-Trélat sign).37

Endocrine Disorders

Alterations in the secretion of endocrine hormones in endocrine disorders may have a variety of GI effects. Most of these produce functional GI symptoms such as vomiting, diarrhea, constipation, and abdominal pain secondary to changes in GI motility (Table 6.1). Most of these diseases do not cause significant morphologic or histologic abnormalities and are described only briefly here.

Adrenal Gland

Addison disease (primary chronic adrenocortical insufficiency) may cause common GI disturbances such as anorexia, nausea, vomiting, and diarrhea.38 Pheochromocytomas are characterized by hypertension due to high catecholamine levels. Intestinal pseudo-obstruction, megacolon, and even bowel ischemia have also been described and are thought to be secondary to the vasoconstrictive action of excess catecholamine levels.39

Hypothalamus and Pituitary

The hypothalamus and pituitary function as a unit. Disorders of either one infrequently affect the GI tract. Hypopituitarism affects intestinal motility, as does hypothyroidism. Pituitary adenomas are part of the multiple endocrine neoplasia (MEN) syndrome, discussed later in this chapter. Of the hyperpituitary lesions, acromegaly is of interest with respect to GI neoplasia. Acromegaly is characterized by chronic hypersecretion of growth hormone and insulin-like growth factor, usually due to a pituitary adenoma. It is associated with overgrowth of the musculoskeletal system and all organs, including the GI tract. Acromegaly has been shown to increase epithelial cell proliferation in the colon,40 and an increased prevalence of colonic adenomas and colonic carcinoma has been observed.41 An increased risk of gastric carcinoma has also been suggested but is less well established.42

Pancreas

Diseases of the exocrine and endocrine pancreas commonly affect the GI tract. These include pancreatic exocrine insufficiency, diabetes, and hormonal effects of functional pancreatic endocrine neoplasms. Pancreatic exocrine insufficiency typically gives rise to steatorrhea and malabsorption and is discussed further in Chapter 39.

Diabetes can involve significant GI symptoms.43 These result from decreased motility secondary to autonomic nervous system dysfunction. Patients have symptoms such as abdominal pain, bloating, early satiety, nausea, and vomiting. Abdominal bloating appears to correlate best with decreased gastric emptying.44 The delayed gastric emptying associated with gastric atony and gastric dilation is called gastroparesis diabeticorum, and an increased risk of bezoar formation is apparent. Patients can also experience periodic intractable diarrhea and crampy abdominal pain. Because of hypomotility, these patients are at risk for bacterial infection and malabsorption. Patients are also at increased risk for Candida infection of the esophagus.45 Histologic features are nonspecific. Neuropathic findings with silver stains have been described,46 as have periodic acid–Schiff (PAS)-positive vascular deposits in the vessels of the submucosa.47

Excess hormonal production from the pancreatic islets of Langerhans can be a result of diffuse hyperplasia (nesidioblastosis) or pancreatic endocrine tumors. Many hormones, such as insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, adrenocorticotropic hormone, calcitonin, parathormone, and serotonin, can be produced by these lesions. All GI manifestations reflect altered digestive function and motility.48

Parathyroid

Both hyperparathyroidism and hypoparathyroidism can cause GI symptoms. GI symptoms occur in half of patients with hyperparathyroidism and may be the presenting symptom in 15% of cases.49 These patients typically have abdominal pain, nausea, vomiting, and constipation. Many of these symptoms are thought to be due to hypercalcemia, which results in altered neuronal transmission and neuromuscular excitability.50 Hypoparathyroidism can be associated with malabsorption and steatorrhea. The small intestinal mucosa is typically histologically normal, but rare associations with celiac sprue have been reported.51

Thyroid

Both hyperthyroidism and hypothyroidism can cause GI symptoms. Hyperthyroidism produces hypermotility of the gut, and hypothyroidism causes hypomotility. Hyperthyroidism can result in rapid gastric emptying, watery diarrhea, and steatorrhea.52 No constant structural changes in the mucosa or in the wall of the bowel have been consistently reported. Hypothyroidism can be associated with gastric bezoar formation, ileus, volvulus, constipation, and megacolon.52 In patients with marked myxedema, dilation and thickening of the bowel wall with microscopic accumulation of mucopolysaccharide substances in the submucosa, muscularis propria, and serosa have been described.53

Thyroid neoplasms may also produce GI effects. Medullary carcinoma of the thyroid is a tumor of the calcitonin-producing endocrine C cells of the thyroid. Patients may have prominent “explosive” watery diarrhea as the result of ectopic hormone production.54 Papillary carcinoma of the thyroid also can be associated with Gardner syndrome.55

Multiple Endocrine Neoplasia

The MEN syndromes are a group of autosomal dominant inherited disorders associated with hyperplasia or neoplasms of several endocrine organs. Three main varieties of this syndrome can occur—MEN I, MEN IIa, and MEN IIb (or III). GI manifestations are caused by the products of endocrine proliferations.56 Each of these syndromes is associated with a mutant gene locus—MEN I with the MEN1 gene locus, and MEN IIa and IIb with the RET gene locus. MEN I is associated with pancreatic endocrine tumors (often gastrinomas) and with the Zollinger-Ellison syndrome, which is associated with gastric and duodenal disease. MEN IIb may be associated with ganglioneuromatosis, ganglion cell hyperplasia, and hypertrophy of the plexuses of Meissner and Auerbach in the GI tract. Chronic constipation, diarrhea, or both may be associated with MEN IIb.57

Hematologic Disorders

Hemorrhagic Disorders

Patients with bleeding disorders may develop spontaneous hemorrhage in any part of the GI tract. Between 10% and 25% of patients with hemophilia suffer from GI hemorrhage.58 Von Willebrand disease,59 heparin or warfarin overdose, vitamin K deficiencies, platelet deficiency, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome (HUS) can all result in hemorrhage of the GI tract. This is most commonly seen in the upper GI tract and typically is most prominent in the submucosa. It can be severe enough to involve the entire thickness of the bowel wall and give rise to an intramural hematoma.60 More severe lesions can cause luminal narrowing, rigidity with obstruction, and, rarely, intussusception.58

Thrombotic Disorders

Sickle cell anemia,61 polycythemia rubra vera,62 and other thrombotic disorders63 can produce thrombosis, leading to infarction and hemorrhage of the intestines. Sickle cell anemia causes sickling of red blood cells and hyperviscosity of the blood and typically produces arterial and capillary obstruction.61 It involves the watershed areas of the distal transverse colon and splenic flexure, which have the lowest oxygen tension. Sickled red blood cells may be found in the vessels. Polycythemia usually leads to venous obstruction of the portal and mesenteric veins. These lesions involve the deeper parts of the bowel wall, including the muscularis propria. Diagnosis is based on the finding of venous thrombi in the mesenteric and mesocolic tissues not in the field of infarction, which occur in conjunction with appropriate clinical history.

Megaloblastic Anemia

Megaloblastic anemias are associated with deficiencies of folic acid and vitamin B12. These anemias are characterized by megaloblastic proliferation of actively growing cells, as is typically described in bone marrow aspirations but is also seen in the epithelial cells of the GI tract. Owing to impaired DNA synthesis, actively dividing cells in the gastric pits, small bowel, and colonic crypts typically show enlarged, immature-appearing nuclei (Fig. 6.2). The nucleus-to-cytoplasm ratio is decreased. The overall numbers of mitotic figures are also reduced. In addition, PAS-negative, Alcian blue–negative cytoplasmic vacuoles have been described in duodenal enterocytes.64 Megaloblastic anemia can be caused by pernicious anemia secondary to autoimmune gastritis; therefore, gastric findings of atrophic autoimmune gastritis may also be present.

Leukemia and Lymphoma

Involvement of the GI tract is often noted in patients with leukemia and lymphoma. This can occur directly by tumor (primary or secondary), secondary to complications of disease, or secondary to therapy (see Chapter 31 for details).

Autopsy studies have revealed GI involvement in 50% of patients with leukemia.65 In secondary involvement of the GI tract by either leukemia or lymphoma, tumor infiltrates are often multifocal and may be present anywhere from the esophagus to the rectum.66 These infiltrates can cause aphthous-type ulcers (typical of leukemic infiltrations) or can result in polypoid, masslike, or large ulcers (typical of lymphomatous involvement).67 The larger mass lesions can occasionally cause obstruction or intussusception.68 Histologic features are those typical of the particular type of leukemia or lymphoma. Malignant cells are typically found in the mucosal and submucosal tissue. Tissue should be collected for molecular and cytogenetic analysis, because many leukemias and lymphomas include diagnostic and clinically important changes.69 Primary lymphomas of the GI tract are often solitary lesions, although diffuse forms do occur (usually in the small bowel).

Secondary effects of tumor overgrowth, or of chemotherapy, resulting in decreased numbers of platelets and inflammatory cells can lead to hemorrhagic lesions of the GI tract and opportunistic infections. In addition, neutropenic colitis, which is a necrotizing inflammatory disorder of the colon that occurs in neutropenic patients, can occur with chemotherapy and, rarely, as a complication of acute leukemia.70 Finally, patients who have received a bone marrow transplant may develop graft-versus-host disease, which is characterized by apoptotic destruction of the epithelium throughout the GI tract. It typically manifests with diarrhea. Histologically, it is characterized by apoptosis of the epithelial cells, followed by crypt and gland loss and, ultimately, mucosal erosion and ulceration.71

Metabolic Disorders

Acrodermatitis Enteropathica

Acrodermatitis enteropathica is a systemic disorder that occurs secondary to zinc deficiency resulting from a congenital defect in absorption of dietary zinc. This disorder has been localized to a gene (SLC39A4) that codes for a transmembrane zinc uptake protein (hZIP4).72 It typically manifests after infancy and weaning (although rare cases have been described in adulthood73). It is characterized by chronic diarrhea associated with failure to thrive, periorofacial dermatitis, paronychia, nail dystrophy, alopecia, susceptibility to infection, and behavioral change. Serum zinc levels are typically decreased. Treatment is provided in the form of oral zinc. Mucosal biopsy of the small bowel can be normal or can show mild, patchy villous lesions. Abnormal inclusion bodies have been described in Paneth cells on electron microscopy.74 Acrodermatitis may also be caused by zinc deficiency secondary to Crohn’s disease75 or malnutrition.76

Plummer-Vinson Syndrome (Paterson–Brown Kelly Syndrome)

The unusual Plummer-Vinson syndrome has shown a recent decrease in incidence.77 It is characterized by iron deficiency (its presumed cause), dysphagia, and esophageal webs.78 Dermatologic findings of angular stomatitis, atrophic tongue, and brittle nails are also seen. Long-standing disease is associated with an increased incidence of postcricoid carcinoma. Iron repletion improves all lesions.

Vitamin Disorders

In general, vitamin disorders are not associated with specific GI symptoms or lesions. Exceptions are brown bowel syndrome, which is thought to be caused by a deficiency of vitamin E (discussed later), and pellagra, which is associated with niacin deficiency (discussed in this section). Multiple vitamin deficiencies are often noted in malabsorptive disorders. Vitamins, macronutrients, and minerals are thought to have a protective effect with respect to neoplasia of the GI tract, especially for esophageal79,80 and gastric81 malignancies. Deficiency in vitamin K or anticoagulation therapy leads to a decrease in coagulation factors and can result in hemorrhagic lesions throughout the body.82 In the GI tract, these range from focal petechial hemorrhages to frank exsanguination. No specific histologic features are associated with these lesions. Similarly, vitamin C deficiency (scurvy) can lead to hemorrhage and delayed wound healing. Deficiencies of folic acid and vitamin B12 are associated with megaloblastic anemia and megaloblastic changes in the epithelial cells of the stomach and small intestine.83 Olestra (a nonabsorbed fat replacement) may decrease the absorption of fat-soluble vitamins.84

Pellagra

Pellagra is a vitamin deficiency that has major GI effects. It is caused by a deficiency of niacin, either dietary (deficiency found in developing countries, alcoholics, and the elderly) or secondary to impaired absorption (e.g., Crohn’s disease,85 amyloidosis86). It is characterized clinically by diarrhea, dermatitis, and dementia. Diarrhea is often bloody. However, patients can have steatorrhea.87 The vitamin deficiency interferes with the normal renewal of epithelial tissue; hence, the effects on the skin and GI tract. Endoscopically, approximately half of patients have lesions. However, all have microscopic inflammation. Endoscopic lesions range from redness and granularity to focal ulceration and more extensive confluent lesions. Microscopically, the inflammatory infiltrate is nonspecific. In the esophagus, mild to severe esophagitis is seen.88 The small bowel may be normal or may show mild villous blunting and increased inflammatory cells in the lamina propria.89 In the large bowel, a mild to moderate inflammatory infiltrate with features of colitis cystica superficialis (cystic dilation of the crypts and crypt abscess formation) has been described. Patients usually respond to niacin replacement therapy.

Lipoprotein Disorders

Abetalipoproteinemia

Abetalipoproteinemia (discussed further in Chapter 9) is an autosomal recessive disorder characterized by a defect in the secretion of plasma lipoproteins that contain apolipoprotein B. Patients have steatorrhea, usually in infancy, with central nervous system symptoms such as disturbance in gait and balance and fatigue.90 On peripheral smear, acanthocytes are usually prominent (in 50% of red blood cells). Laboratory findings show an absence of very-low-density lipoproteins, the presence of chylomicrons, and a reduction in triglycerides and other lipids. The defect occurs in a microsomal triglyceride transfer protein required for the secretion of plasma lipoproteins containing apolipoprotein B.91 Normal intraluminal digestion of lipids occurs, along with transport of triglycerides and monoglycerides and their reesterification in enterocytes. However, lipids cannot be excreted on the basal lateral membrane of the enterocytes into blood and lymphatics. Histologically, this translates into prominent accumulation of fine lipid droplets within the basal aspect of the enterocytes (Fig. 6.3). These can be stained with Oil Red O on frozen-section tissue or seen by electron microscopic examination. The overall architecture of the small bowel is normally well maintained. One pitfall in diagnosis is the similar appearance of lipid droplets identified in normal individuals after a recent lipid-rich meal; therefore, the diagnosis should be made only in fasting patients.

Tangier Disease

Tangier disease is an autosomal recessive disorder characterized by deposition of cholesteryl esters in the reticuloendothelial system, almost complete absence of high-density lipoprotein in the plasma, and aberrant cellular lipid trafficking.92 Clinically, patients present with hepatosplenomegaly, enlarged tonsils, peripheral neuropathy, and, occasionally, diarrhea. Laboratory studies reveal low blood levels of high-density lipoprotein and cholesterol (due to lack of apoprotein A) and high levels of triglycerides. Endoscopically, the lesions are described as tiny yellow nodules or orange-brown spots.93 Microscopic examination reveals clusters of foamy histiocytes in the lamina propria (Fig. 6.4). Electron microscopic findings include intracytoplasmic vacuoles unbounded by membranes; these are often confluent in appearance94 (see Chapter 9 for details).

Lysosomal Storage Disorders

Lysosomes, which are a major component of the intracellular digestive tract, contain hydrolytic enzymes made in the endoplasmic reticulum. These enzymes break down a variety of complex macromolecules that are either a component of the cell or are taken up by phagocytosis. Lysosomal storage disorders are inherited disorders (usually autosomal recessive) caused by lack of a functional enzyme or defective enzyme lysosome targeting. Substances typically accumulate within cells at the site where most of the degraded material is found; degradation typically occurs at this location.

Storage disorders can be divided based on the biochemical nature of the accumulated metabolite into glycogenoses, sphingolipidoses (lipidoses), mucopolysaccharidoses, mucolipidoses, and others. Most of these diseases have prominent central or peripheral nervous system effects.95 Except for Fabry disease, they do not have significant GI effects. Case reports of malabsorption in GM1 gangliosidosis,96 diarrhea in Niemann-Pick disease,97 and diarrhea and vomiting in Wolman disease have been described.98

The importance of these diseases is that depositions can be identified in a variety of cells in the GI tract (Table 6.2), typically in the phagocytic cells (macrophages) in the lamina propria. The histologic appearance typically reveals an accumulation of cells with foamy cytoplasm. The material may be positive for fat stains such as Oil Red O or Sudan black on frozen-section tissue or PAS stain, depending on the particular substance that has accumulated. Electron microscopic examination typically reveals enlarged, unusually shaped lysosomes. Historically, many of these diagnoses have been made on rectal biopsy with histochemical stains and subsequent electron microscopic examination.99101 This technique has largely been supplanted by specific enzyme content analysis of circulating lymphocytes or biopsy material. Differentiation among the common mimics of storage disorders is described in the next section.

Table 6.2

Lysosomal Storage Diseases

Disease Enzyme Deficiency Major Accumulating Metabolite GI Symptoms Affected Cells Histologic Features Electron Microscopic Features
Glycogenoses
Type 2 Pompe disease α-1,4-Glucosidase Glycogen None Hepatocytes, cardiac and skeletal muscle cells Glycogen within sarcoplasm, PAS positive Glycogen
Sphingolipidoses
GM1 gangliosidosis GM1 ganglioside β-galactosidase GM1 ganglioside Malabsorption Neurons Ballooned neurons, fat stain positive Whorled configurations
GM2 Gangliosidosis
Tay-Sachs disease Hexosaminidase α subunit GM2 ganglioside None Neurons Ballooned neurons, fat stain positive Whorled configurations
Sandhoff disease Hexosaminidase β subunit GM2 ganglioside None Neurons Ballooned neurons, fat stain positive Whorled configurations
Variant AB Ganglioside activator protein GM2 ganglioside None Neurons Ballooned neurons, fat stain positive Whorled configurations
Sulfatidoses
Metachromatic leukodystrophy Arylsulfatase A Sulfatide None Phagocytic cells Inclusions stain with toluidine blue or other metachromatic stains Free lipid bodies without cytosomes
Multiple sulfatase deficiency Arylsulfatases A, B, C Sulfatide, heparan sulfate, dermatan sulfate None Phagocytic cells Inclusions stain with toluidine blue and other metachromatic stains Zebra bodies
Krabbe disease Galactosylceramidase Galactocerebroside None Phagocytic cells Globoid PAS-positive cells Curved tubular inclusions
Fabry disease α-Galactosidase A Ceramide trihexoside Delayed gastric emptying Phagocytic, ganglion, endothelial cells, smooth muscle fibers Vacuolization, fat stain positive Zebra bodies
Gaucher disease Glucocerebrosidase Glucocerebroside None Phagocytic cells Fibrillary cytoplasm (tissue paper–like), PAS positive Elongated lysosomes, stacks of bilayers
Niemann-Pick disease Sphingomyelinase Sphingomyelin Diarrhea Phagocytic cells, axons, Schwann cells Innumerable small, uniform vacuoles, PAS positive Zebra bodies
Mucopolysaccharidoses (MPS)
Hurler syndrome (MPS I) α-l-Iduronidase Dermatan sulfate, heparan sulfate None Phagocytic cells, endothelial cells fibroblasts Balloon cells, PAS positive Lamellated zebra bodies
Hunter syndrome (MPS II) l-Iduronidase sulfatase Dermatan sulfate, heparan sulfate None Phagocytic cells, endothelial cells, intimal cells, fibroblasts Balloon cells, PAS positive Lamellated zebra bodies
Mucolipidoses (ML)
I-cell disease (ML2) Mannose-6-phosphate phosphorylating enzyme Mucopolysaccharide, glycolipid None Gastric chief cells, enterocytes Vacuolated cells, PAS and fat stain positive Enlarged lysosomes
Other
Cystinosis Cystine Cystine transported None Phagocytic cells Polarizable crystals, unfixed specimen Membrane-bound crystals
Mannosidosis Oligosaccharides Mannosidase None Phagocytic cells, nerve and muscle cells, fibroblasts Small vacuoles, PAS positive on frozen section only Small membrane-bound bodies with fibrillar material
Neuronal ceroid lipofuscinosis (Batten disease and Kufs disease) Unknown Ceroid or lipofuscin-like protein None Phagocytic cells, some muscle and Schwann cells, endothelial cells Large, coarse, granular pigment, positive for Sudan black, PAS, acid-fast, yellow autofluorescence Globules with a granular matrix, “Finnish snowballs”
Wolman disease Acid lipase Cholesterol esters, triglycerides Diarrhea, vomiting Phagocytic cells Large lipid vacuoles, fat stain positive Membrane-bound lipid droplets

image

GI, Gastrointestinal; PAS, periodic acid–Schiff stain.

Fabry Disease

Fabry disease is a rare, X-linked lipid storage disorder that is caused by a deficiency of lysosomal α-galactosidase A and results in cellular deposition of glycolipids in many tissues. Clinically, these patients have involvement of multiple organ systems. Symptoms include excruciating pain in the extremities (acroparesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke, and renal failure.102 GI symptoms are seen in 62% of male and 29% of female heterozygotes.103 Features include vascular ectasia,104 delayed gastric emptying,105 diarrhea, and, rarely, ischemic bowel disease with perforation.106 Histologically, glycolipid deposition is identified in vacuolated ganglion cells in the Meissner plexus and in small blood vessels. By electron microscopy, laminated and amorphous intralysosomal, “zebra-like,” osmiophilic deposits occur in ganglion cells, smooth muscle fibers, and endothelial cells.103

Common Mimics of Lysosomal Storage Diseases

Common mimics of lysosomal storage diseases are summarized in Table 6.3. These are divided into two general categories—pigmented and nonpigmented. The majority of lesions result from a proliferation of histiocytes with either engulfed infectious organisms or cellular or extracellular material. Pigmented lesions, which are in the differential diagnosis of neuronal ceroid lipofuscinosis, include mela­nosis, pseudomelanosis, brown bowel syndrome, hemosiderosis, and barium granuloma. Nonpigmented lesions are in the differential diagnosis of all of the rest of the lysosomal storage diseases and include xanthoma, muciphages, Whipple disease, Mycobacterium avium-intracellulare complex (MAC) infection, pseudolipomatosis, malakoplakia, granular cell tumors, signet ring adenocarcinoma, and malignant histiocytosis.